This proposal will examine they hypotheses that macrosomia at birth, in infants born to diabetic mothers, is related to fetal hyperinsulinemia which may be of endogenous origin, or exogenously transferred to the fetus as antibody-bound insulin. The exogenously transferred beef-pork insulin will be measured via newly established techniques using high performance liquid chromatography in a unique "library" of cord sera accumulated from the ongoing Diabetes in Pregnancy Program Project Grant. We postulate that endogenous fetal hyperinsulinemia, resulting from beta cell hypertrophy/hyperplasia secondary to excessive nutrient transfer from the mother, causes a long-lasting "metabolic imprint". This imprint is manifested by persistent post-natal insulin hyper responsiveness to secretagogues such as glucose.- In time, hyperinsulinemia induces "compensatory" resistance to insulin action, more apparent for glucose than lipid metabolism, and eventually results in a higher prevalence of obesity with a characteristic centripetal fat distribution. This hypothesis will be tested by examining insulin secretion and insulin sensitivity via the so-called minimal model technique. This approach uses a computer program to analyze the glucose and insulin responses to a modified intravenous glucose tolerance test. Anthropometric measurements including skinfold thickness, and bioelectrical impedance will be used to assess body composition and fat free mass. We postulate that children who were macrosomic at birth due to antibody bound insulin transferred from the mother should not manifest persistent metabolic abnormalities. In all studies, children who were born to diabetic mothers will be compared to appropriate. age-matched controls born to non-diabetic mothers. These studies may demonstrate whether endogenous fetal hyperinsulinemia causes permanent metabolic changes in later life that may predispose to obesity or other sequelae. The studies may also provide a rationale for the use of highly purified insulins in pregnant diabetics to minimize antibody response and antibody transferred insulin that may cause macrosomia.